Marc Zarefsky, October 9, 2016

Across the globe, the most frequent form of diagnosed cancer is breast cancer. Nearly 75% of those diagnoses feature tumors that test positive for estrogen receptors (ER), a group of proteins within the cancer cells that are activated by estrogen.

Tamoxifen is one of the best drugs to fight against breast cancer and has been for more than 40 years, according to University of Illinois Researcher Zeynep Madak-Erdogan. But not all patients react the same way to tamoxifen.

Madak-Erdogan and a team of Illinois researchers recently discovered why.

In an article published online in the Journal of Molecular Endocrinology, the team shares that patients with high levels of several specific nuclear transport genes are more likely to be resistant to tamoxifen. With that knowledge, the team discovered that combining tamoxifen with selinexor - a second drug that prevents the activity of one of those genes - increases patients? sensitivity to tamoxifen and prevents the recurrence of breast tumors.

Madak-Erdogan took time to talk about her team?s findings and the impact they can have.

BTN LiveBIG: Who are the primary patients likely to use tamoxifen?

Zeynep Madak-Erdogan: Tamoxifen is the drug of choice for premenopausal women and postmenopausal women who cannot tolerate side-effects of other hormone therapy alternatives to prevent or treat early stage breast cancer.

BTN LiveBIG: Are there alternative therapies that work like tamoxifen?

ZME: While tamoxifen doesn?t work equally well for all patients whose tumors express the estrogen receptor, alternative therapies for ER+ patients, such as aromatase inhibitors that also target the estrogen signaling pathway, may cause significant adverse side effects such as increased joint pain, bone fractures or increased heart disease risk.

In contrast to tamoxifen, these alternative therapies may also be less effective at reaching the tumors they are meant to treat. Thus, tamoxifen remains an important therapy agent for both pre- and post-menopausal women, and tamoxifen is expected to continue to be a standard of care for patients with ER+ disease.

BTN LiveBIG: What excites you most about your key findings?

ZME: We found the machinery that controls transport of proteins to the nucleus was regulated by tamoxifen and other ER ligands. However, when cancer cells became resistant to tamoxifen, the level of XPO1 - one of the key proteins that move proteins out of the nucleus - was very high.

What is very exciting about our findings is that XPO1 is already targeted using a very specific small molecule inhibitor in phase III clinical trials in prostate cancer and leukemia. It means that we can translate our results to clinic in a very short time.

BTN LiveBIG: How will your findings help cancer patients?

ZME: Our research will help cancer patients in two ways: we now have a way to identify patients who will respond positively to tamoxifen, and we identified combinations of drugs that can overcome resistance to tamoxifen.

Since we have found that tamoxifen?s effectiveness can be decreased when certain proteins are pumped out of the cell?s nucleus, we will study one protein, XPO1, that is responsible for moving proteins out of the nucleus. With a better understanding of how XPO1 works, we can make tamoxifen work better for breast cancer patients.

These studies will directly benefit the breast cancer community by reducing the mortality of patients as we enable oncologists to better select treatment strategies based on whether a patient will respond best to tamoxifen alone or in conjunction with another therapeutic agent. Indirect benefits include reduced exposure to alternative treatment side effects, greater understanding for patients of why their tamoxifen treatment did or did not work for them, new options for those with breast cancer recurrence, and new hope for tamoxifen-resistant patients.

There are many patients with metastatic ER+ tumors that do not respond to other hormonal treatments. We would like to perform a small-scale clinical trial with a combination of the XPO1 inhibitor - selinexor - and tamoxifen in these patients.

We are looking at a timeline of one to two years to move this into a clinical trial.

BTN LiveBIG: Do you think your findings could lead to benefits for other cancer patients?

ZME: Our work provides a framework for the role of XPO1 in drug resistance that can be applied beyond the ER+ model system to ER-negative breast cancers and even malignancies in other parts of the body.